1,1&#39;-azo bis(1h-imidazo(1,2-a)pyridinium dibromide compounds

ABSTRACT

THERE ARE PROVIDED COMPOUNDS OF THE GENERAL FORMULA   (2-R3,3-R4,4-R2,5-R1-1H-IMIDAZOL-1-YL)2-N2 (X(-))2   IN WHICH R1-R4 WHICH MAY BE THE SAME OR DIFFERENT REPRESENT LOWER ALKYL, LOWER ALKENYL, HALOGEN, ARALKYL OR ARYL IN WHICH THE ARYL GROUP MAY BE SUBSTITUTED WITH HYDROXY, LOWER ALKOXY, HALOGEN, NITRO OR TRIFLUOROMETHYL AND IN WHICH ANY TWO ADJACENT GROUPS R MAY TOGETHER WITH 2 ATOMS OF THE IMIDAZOLE RING FORM A 5, 6 OR 7 MEMBERED CARBOCYCLIC OR HETEROCYCLIC RING; AND X REPRESENTS A PHYSIOLOGICALLY ACCEPTABLE ANION. THESE COMPOUNDS HAVE A CURARE LIKE NEUROMUSCULAR BLOCKING ACTION.

United States Patent 3,773,746 1, '-AZO BIS(1H-IMIDAZO(1,2-a) PYRIDINIUM DIBROMIDE COMPOUNDS David Jack, London, and Ernest Edward Glover, Middlesbrough, England, assignors to Allen & Hanburys Limited, London, England No Drawing. Filed May 13, 1971, Ser. No. 143,210 Claims priority, application Great Britain, June 3, 1970,

2/ 70 Int. Cl. A611 27/ 00; C07c 115/00 US. Cl. 260-140 13 Claims ABSTRACT OF THE DISCLOSURE There are provided compounds of the general formula R2 R1 R1 R This invention relates to novel imidazolium salts and to pharmaceutical compositions containing the same.

We have found that certain imidazolium salts which are new, have an interesting pharmacological activity and in particular have a curare like neuromuscular blocking action and may therefore be used to produce relaxation during anaesthesis or to prevent convulsions in electroconvulsive therapy.

These compounds are found to have several advantageous properties including being rapid in onset, having a shorter action than a-tubocurarine, and not producing the idiosyncratic responses in patients suiTering from cholinesterase deficiencies that can accompany the use of succinyl choline, nor the cardiovascular responses associated with a-tubocurarine.

The present invention provides imidazolium derivatives of the General Formula I:

in which R -R may be the same or different, are lower alkyl (1-6 carbon atoms) lower alkenyl (2-6 carbon atoms), halogen, aralkyl or aryl. The aryl group may optionally be substituted by hydroxy, lower alkoxy, halogen, nitro or trifluoromethyl, or in which any two adjacent groups R together with two atoms of the imidazole ring, form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, and X may be any physilogically aceptable anion such as bromide, chloride, acetate, phosphate, perchlorate or picrate.

Preferred compounds are those in which R and R represent hydrogen, alkyl containing 1-3 carbon atoms, halogen, phenyl or halophenyl and R and R together with the atoms of the imidazole ring form a pyridinium or tetrahydropyridinium group.

The invention also provides pharmaceutical compositions which contain a salt of General Formula I, together with a pharmaceutically acceptable carrier. The most usual means of administering neuromuscular blocking agents is by intravenous injection, although other parenteral routes may sometimes be used. Injections may be formulated with the aid of physiologically acceptable carriers and agents as solutions, suspensions or as dry products for reconstitution before use.

A suitable single injectable dosage range is about 2 to 100 mgs. but continuous infusion or repeated injections may be needed for long operations.

The compounds of the invention possess a short lasting curare-like neuromuscular blocking action. The desirability of a shortacting muscle relaxant is well known. For long operations an adequate level of relaxation can be obtained by continuous intravenous drip, thereby giving the anaesthetist a greater control of the degree of relaxation and also allowing a rapid return to spontaneous movement when the infusion is stopped. The short acting muscle relaxants at present in use are of the depolarising type and have several disadvantages. Post-operative pain constitutes one of the major disadvantages in the use of succinylcholine. Its occurrence is associated with depolarisation and may be a consequence of the muscle fasciculations which occur during onset. Other disadvantages are the lack of a suitable antagonist and the possibility of prolonged apnoea.

A preferred compound of the invention is LI -azobis- [3-methyl 2 phenyl 1H imidazo[l,2-a]pyridinium] dibromide of Example 4.

Equipotent neuromuscular blocking doses of succinylcholine and l,l -azobis[3-methyl-2-phenyl-lH-imidazo- [1,2-a]pyridinium]dibromide have similar durations of activity in the anaesthetized cat but what is particularly striking is the rapid recovery from blockade with the compound of the present invention even when the drug has been infused for long periods of time. The neuromuscular blocking activity of some compounds of our invention in v the cat art summarised in the table below.

Cat sciatic nerve-tibialis muscle preparation.

-100% inhibition, mg./kg. 1,1 azobis[2 phenyl 1H imidazo[1,2 -a

pyridinium1dibromide of Example 2 0.2-0.5 1,1 azobis[3 methyl 2 phenyl 1H- imidazo 1,2-a]pyridinium] dibromide of Example 4 0.1-0.2 Succinylcholine 0.04-0.08

(+)-tubocurarine 0.1-0.4

The reaction is preferably efiected in a solvent such as, for example, water or ethanol below 10 C. e.g. 0 C.

The invention therefore provides a process for the preparation of compounds of Formula I according to the invention which comprises subjecting a compound of For 2 Hal 4 Hal R R2 9 4 N gum a Hal I H o l e- 2 N 1 N 3 n a a a m NH CO-CH:

R /H R1 /R N 1 Na/llq NH; I N 1 nmosoan L l 2 R4 Hal R 1 2 n Hal Hal 3: e 4

S/ R. J

N m-co-dH-m 69 I up N f NH/\R' I I IH 3 NH lHa (IV) CH:

The imidazole III and the hydrazamidine 1V may be prepared by any of the numerous routes known to those skilled in the art.

The nature of the R R may result from using starting materials containing appropriate groups or they may be changed after the preparation of the compound of Formula I by a reaction such as that indicated below to convert R =H into R =Br.

Also the amine of Formula II may be subjected to a reaction to change the nature of the groups R -R Thus when R and R together with two atoms of the imidazole ring represent a pyridine ring the latter may be converted COCH into a tetrahydropyridine ring by hydrogenation with a platinum catalyst.

The following examples illustrate the invention:

EXAMPLE 1 1,1 -azobis lH-imidazo 1,2-a] pyridinium] dibromide (a) 2-(2 acetylhydrazino)pyridine.-2 hydrazinepyridine (1.5 g.) was treated with a mixture of pyridine (6 ml.) and acetic anhydride (1.5 ml.) and the solution allowed to stand for hour. The acetylating mixture was then removed under reduced pressure and the residue washed with dry ether giving the colourless monoacetyl derivatives (1.625 g.) M.P. ISO-154. The melting point was unchanged after recrystallization from benzene.

(b) 2 (2 acetylhydrazino) 1 formylmethyl pyridinium bromide.A solution of 2-(2-acetylhydrazino)- pyridine (0.73 g.) in methanol (2.5 ml.) was treated with freshly distilled bromoacetaldehyde (0.825 g.) and the mixture allowed to stand overnight. The mixture was then warmed on a water bath and dry ether added into incipient precipitation. The bromide (1.165 g.), separated on cooling and crystallized from ethanol-ether as colourless prisms, M.P. 191. The picrate crystallized from ethanolether as yellow needles, M.P. 151.

(c) 1 aminoimidazo(l,2-a)pyridinium bromide.--A solution of the monoquaternary salt prepared in (b) (1.63 g.) in 24% hydrobromic acid (10 ml.) was boiled under reflux for 1 hour. The solution was evaporated to dryness under reduced pressure and the residual bromide was recrystallized from ethanol-ether giving pale yellow prisms, M.P. 163-l64 (1.19 g.). The picrate crystallized from water as yellow needles, M.P. 165.

(d) l,l azobis[lH imidazo[1,2-a]pyridinium]dibromide.Ice-cold saturated bromine water (7 ml.) was added to an ice cold solution of 1-aminoimidazo(l,2-a)- pyridiniurn bromide (0.06 g.) in water (0.5 ml.). The yellow-orange solid which immediately precipitated was filtered off and washed with a little ice-cold water. It was then boiled in anhydrous acetone (2 ml.) until the solid became pale yellow in colour; a little more acetone was then added to ensure complete precipitation. The pale yellow dibromide (0.03 g.), recrystallized from hydrobromic acid (48%)-methanol giving the monohydrate as yellow prisms, M.P. 309 (decomp.). The diperchlorate crystallized from water as the monohydrate, M.P. 290. The dipicrare crystallized from nitromethane as yellow needles, M.P. 279.

EXAMPLE 2 1,1 -azobis[2-phenyl-1H-imidazo[ 1,2-,a]pyridinium] dibromide (a) 2-(2-acetylhydrazino)-1-phenacyl pyridinium bromide.-A solution of 2-(2-acetylhydrazino)pyrimidine (0.3 g.) and phenacylbromide (0.4 g.) in acetone (5 ml.) was boiled under reflux for 5% hours after which time it was cooled and filtered. The colourless bromide (0.52 g.) crystallized from ethanol-ether as colourless prisms, M.P. 171. The picrate crystallized from nitromethane as yellow needles, M.P. 115.

(b) 1 amino-2-phenylimidazo(1,2-a)pyridinium bromide.A solution of the monoquaternary salt as prepared in (a) above (0.19 g.) in 24% hydrobromic acid (2 ml.) was boiled under reflux for 1 hour. The solution was cooled and the bromide (0.15 g.) was filtered off. Recrystallization from ethanol-ether gave the monohydrate as colourless needles, M.P. 177-179. The picrate crystallized from water as yellow needles, M.P. 158-162".

(c) 1,l -azobis[2-phenyl 1H imidazo[l,2-a]pyridinium]dibromide.-Saturated bromine water (7 ml.) was added to a solution of 1-arnino-2-phenylimidazo(1,2-a)- pyridinium bromide (0.06 g.) in water (0.05 ml.). The orange-red solid which precipitated was filtered washed with a little ice-cold water and boiled for 2 minutes in anhydrous acetone (2 ml.). After the addition of a little more acetone to ensure complete precipitation the dibromide (0.037 g.) was filtered off and recrystallized from methanol-ether giving yellow prisms, M.P. 253-255 (decomp.). The dipicrate crystallized from nitromethane as yellow prisms, M.P. 205 (decomp.).

EXAMPLE 3 1,1 -azobis[3-bromo-2-methyl-lH-imidazo 1 ,2 -a] pyridinium] dibromide (a) 1 acetonyl-2-(2-acetylhydrazino)pyridinium bromide.A solution of 2-(Z-acetylhydrazino)pyridine (0.3 g.) and bromoacetone (0.275 g.) in absolute alcohol (5 ml.) was boiled under reflux for 5 hours. The solution was cooled, ether added to initiate precipitation and the solution stood overnight in a refrigerator. The separating bromide (0.35 g.) was filtered oif. Recrystallization from nitromethane-ether gave an amorphous solid, M.P. 167- 168. The picrate crystallized from water as yellow prisms, M.P. 200-202".

(b) 1 amino-Z-methylimidazo(1,2-a)pyridinium bromide.A solution of the monoquaternary salt as prepared in (a) above (0.225 'g.) in 24% hydrobromic acid (4 ml.) was boiled under reflux for 1 hour. The solution was evaporated to dryness under reduced pressure and the residue was dissolved in methanol. The bromide (0.16 g.) was precipitated by the addition of ether and recrystallized from ethanol-ether as colourless needles, M.P. 224-225 The picrate crystallized from ethanol as yellow prisms, M.P. 145-146".

(c) 1,1 -azobis-3-bromo-2-methyl-1H imidazo[l,2-a] pyridinium dibromide.-Ice cold saturated bro-mine water (7 ml.) was added to a solution of l-amino-2-methylimidazo(l,2-a)pyridiniurn bromide (0.06 g.) in water (0.5 ml.) and the precipitated yellow-orange solid filtered 01f and washed with a little ice-cold water. The solid was then boiled in anhydrous acetone (2 ml.) until its colour changed to pale yellow. After the addition of a little more acetone the dibromide (0.033 g.) was filtered off and recrystallized from methanol giving yellow needles, M.P. 257. The dipicrate crystallized from water as orangeyellow plates, M.P. 207.

6 EXAMPLE 4 1,l -azobis[3-methyl-2-phenyl-lH-imidazo[1,2-a] pyridinium1dibromide (a) 1 acetamido 3 methyl 2 phenylimidazo- [l,2-a]pyridinium bromide.-A mixture of 2-(2-acetylhydrazino)pyridine (.2 g.) and 2-bromopropiophenone (2.84 g.), in ethanol (10 ml.) was heated in an open flask in a bath at 160-170 until the ethanol had evaporated; the residual melt was then heated for a further 0.25 h. After cooling, the residual gum was triturated with acetone and the resulting solid (2.8 g.) recrystallized from ethanol-ether giving the bromide as colourless prisms, M.P. 232-234".

(b) 1 amino 3 methyl 2 phenylimidazo[1,2-a] pyridinium bromide-A solution of the acetamido compound (2.78 g.) in 24% hydrobromic acid (12 ml.) was boiled under reflux for 1 h. The solution was then evaporated under reduced pressure and the residue dissolved in methanol. Addition of ether precipitated the bromide which crystallized from ethanol as colourless prisms, M.P. 243-244 (1.7 g.).

(0) 1,1 azobis[3 methyl 2 phenyl 1H imidazo[l,2-a]pyridinium]dibromide.A warm (50) solution of the N-amino compound (0.6 g.) in water (10 ml.) was treated with saturated bromine water (70 ml.) and the precipitated orange solid filtered off and washed with water. The orange solid was sucked dry and then boiled with acetone (30 ml.) until the suspended solid became yellow. Absolute acetone 10 ml.) was then added and the solution filtered giving the dibromide (0.57 g.) which crystallized from water as the yellow dihydrate, M.P. 215-219 (softened at 196). Tre dipicrate crystallized from nitromethane-ether as yellow prisms, M.P. 189-191 (decomp) 1,1 azobis[3 methyl-Z-phenyl-lH-imidazo- [l,2-a]pyridinium]dibromide may also be prepared as follows:

(a) 1 acetamido 3 methyl 2 phenylimidazo( 1,2- a)pyridinium bromide.-2 (2 acetylhydrazino) pyridine (4.4 g.) 2-bromopropiophenone (6.0 g.) were heated and stirred in nitrobenz/ene (40 ml.) at for 3 days. The solution was then cooled and ether (200 ml) was added to precipitate a brown gum. After triturating with more ether this was crystallized from ethanol/ethyl acetate to give a white crystalline solid (3.5 g.) M.P. 228-30.

(b) 1 amino 3 methyl 2 phenylimidazo(1,2 a) pyridinium bromide.-The acetamido compound (3.5 g.) was heated at reflux in 25% aqueous hydrobromic acid for 4 hrs. The solution was then evaporated to dryness in vacuo and the residue crystallized from ethanol/ethyl acetate to give the product as a white crystalline solid (2.2 g.) M.P. 240.

(0) 1,1 azobis[3 methyl 2 phenyl 1H- imidazo- (1,2-a)pyridinium]dibromide.The amino quaternary compound (2.0 g.) was dissolved in warm water (50 ml.) and added rapidly to a vigorously stirred solution of bromine (3 ml.) in ice/water (250 ml.). After stirring for 20 mins. benzene ml.) was added and after a further 20 mins. the orange solid was filtered ofl. This was immedidately stirred and heated at reflux in acetone (200 ml.). The pale yellow solid was filtered olf, dried and crystallized from methanol/ ethyl acetate to give the product as a yellow solid (1.2 g.) M.P. 218-220.

EXAMPLE 5 1,1 -azobis[3-bromo-2-phenyl-lH-imidazo[ 1,2-a] pyridinium] dibromide (a) 1-amino-3-bromo-2-phenylimidazo[1,2-a]pyridiniurn bromide.A solution of the N amino compound from Example 2(b) (0.25 g.) in water (20 ml.) at 5 was treated with saturated bromine water (29 ml.).

The precipitated solid was filtered 01f and boiled with acetone and the dibromide as in Example 2 (0.14 g.) filtered ofl. Evaporation of the filtrate under reduced pressure and at room temperature followed by treatment of the residue with methanol-ether gave thebromocompound (0.023 g.) which crystallized from water as colourless needles, M.P. 236 (decomp).

(b) 1,1 -azobis[3 bromo 2 phenylirnidazo[1,2-a] dibromide.A solution of the bromide (0.15 g.) in warm (35) water (3 ml.) was treated with saturated bromine Water (16.5 ml.). The reaction mixture was gently stirred until the precipitate co'agulated when the orange solid was filtered off, washed once with water and then boiled in acetone until the solid became pale yellow. The filtered dibromide (0.12 g.) crystalized from methanol-ether as yellow prisms, M.P. 220. The dipicrate crystallized from nitromethane and had M.P. 175-178" (decomp.).

1,l -abobis[3 bromo 2 phenyl 1H imidazo[l,2-a] pyridinium] dibromide may also be prepared as follows:

(a) 1 amino 3 bromo 2 phenylimidazo(1,2-a) pyridinium bromide.l amino 2 phenylimidazo (1,2a)pyridinium bromide (14.5 g.) was stirred in methanol (100 ml.) and bromine (6 ml.) was added rapidly. A yellow solid precipitated. This was filtered ofl and washed with methanol. This crude perbromide was immediately heated at reflux in acetone (500 ml.) when a clear solution was obtained. The acetone solution was evaporated in vacuo and the residue crystallized from methanol/ethyl acetate to give the required product (9.8 g.), M.P. 236.

(b) l,1 -azobis[3 bromo 2 phenyl 1H imidazo (1,2-a)pyridinium]dichloride.1 amino 3 bromo- 2-phenylimidazo(1,2-a)pyridinium bromide (9.8 g.) was dissolved in hot water (200 ml.) and added rapidly to a vigorously stirred solution of bromine (14 ml.) in ice/ water (1200 ml.) After 30 minutes a mixture of benzene (200 ml.) and petroleum ether (B.P. 60-80") (50 ml.) was added. After a further 30 minutes the solid was filtered ofl. This orange solid was immediately heated at reflux in acetone (200 ml.) and the bright yellow solid was filtered ofi and dried to give the dibromide of the product (7.0 g.).

The crude dibromide (3.7 g.) was suspended and stirred in water (40 ml.) and silver acetate (1.7 g.) was added.

After ca. 30 minutes the silver bromide was removed by filtration and an excess of hydrochloric acid was added. The small amount of silver chloride was filtered off and the clear solution was evaporated in vacuo. The solid residue was crystallised from methanol/ethyl acetate to give the required dichloride (2.5 g.), M.P. 230 (decomp.).

EXAMPLE 6 1, l -azo'bis [2- (p-bromophenyl -1H-imidazo[ 1,2-a] pyridinium] dibromide (a) 2 (2 acetylhydrazino) 1 (bromophenacyl) pyridinium bromide.A solution of 2-(2-acetylhydrazino) pyridine (0.45 g.) and p-bromophenacyl bromide (0.83 g.) in acetone (8 ml.) was boiled under reflux for 2.5 h., the reaction mixture cooled and the product (0.7 g.) filtered off. Recrystallization from ethanol-ether gave the colourless bromide, M.P. 202-203.

(b) 1 amino 2 (p bromophenyl)imidazo[1,2-a] pyridinium bromide.A solution of the quaternary salt (0.7 g.) in 24% hydrobromic acid (8 ml.) was boiled under reflux for 1 h., the reaction mixture cooled and the product (0.59 g.) filtered olf. Recrystallization from ethanol gave the colourless bromide as the monohydrate, M.P. 238-239".

(c) 1,1 azobis 2 (p bromophenyl 1H imidazo [1,2-alPYridinium dibromide.A warm (50) solution of the N-amino compound (0.6 g.) in water was treated with saturated bromine water (6 ml.) The precipitated orange solid was filtered off and boiled with acetone until it became pale yellow in colour. The yellow dibromide (0.46 g.) was filtered off and after recrystallization from 8 methanol-ethanol had M.P. 206-207. The dipicrate crystallized from nitromethane as yellow prisms, M.P. ZOO-201 (decomp.).

EXAMPLE 7 1,1 azobis[2-methyl-3-phenyl-lH-imidazo[1,2-a] pyridiniumJdibromide (a) 2 (2 acetylhydrazino) 1 (2 oxo 1 phenylpropyl)pyridinium bromide.A solution of 2-(2-acetylhydrazino) pyridine (1.55 g.) and the appropriate bromoketone (2.74 g.) in acetone (20 ml.) was boiled under reflux for 18 h. The reaction mixture was cooled, the white solid filtered off and washed with acetone. Recrystallization of the solid from ethanol-ether gave the colourless bromide, M.P. 186188 (2.4 g.).

(b) 1 amino 2 methyl 3 phenylimidazo[1,2-a] pyridinium bromide.A solution of the quaternary salt (2.04 g.) in 24% hydrobromic acid (10 ml.) was boiled under reflux for 1 h. The solution was evaporated under reduced pressure and the residue crystallized from ethanol-ether giving the colourless bromide, M.P. l75 176 (0.43 g.).

(c) 1,1 azobis[2 methyl 3 phenyl 1H imidazo [1,2-a]pyridinium dibromide.A warm (50) solution of the N-amino compound (0.74 g.) in water (23 ml.) was treated with saturated bromine water (93 ml.). The precipitated red solid was filtered oil and boiled with acetone until the suspended solid became pale yellow. The yellow solid was filtered chi and recrystallised from methanol-ether giving the yellow dibromide, M.P. 240 (decomp.) (0.4 g.).

EXAMPLE 8 1, 1 -azobis [2,3-diphenyllH-imidazo 1,2-a] pyridinium] dibromide (a) 2(2 acetylhydrazino) 1 (a phenylphenacyl) pyridinium bromide.A solution of 2 (2 acetylhydrazino)pyridine (1.64 g.) and a-phenylphenacyl bromide (3 g.) in acetone (30 ml.) was boiled under reflux for 50 h. The cooled reaction mixture was treated with ether and the precipitated solid filtered ofi. Crystallization of the solid from aqueous acetone gave the bromide (0.85 g.) which recrystallized from water as colourless prisms, M.P. -176.

(b) 1 amino 2,3-diphenylimidazo[1,2-a]Pyridinium bromide.A solution of the quaternary salt (0.8 g.) in 24% hydrobromic acid (10 ml.) was boiled under reflux for 1 hr. The solution was then evaporated under reduced pressure and the residue crystallized from methanolether giving the yellow bromide (0.515 g.), M.P. 240- 245" (decomp.).

(c) 1,1 -azobis[2,3-diphenyl 1H-imidazo[1,2-a]pyridinium] dibromide.A warm (60) solution of the N- amino compound (0.06 g.) in water (2 ml.) was treated with saturated bromine water (2 ml.), the precipitated red solid was filtered off and boiled with acetone until the solid became yellow. The yellow solid (0.05 g.) was filtered off and recrystallised from methanol-ether giving the dibromide as the yellow mono-hydrate, M.P. 209- 210.

EXAMPLE 9 1,1 -azobis[5 ,6,7,S-tetrahydro-Z-phenyllH-imidazo 1,2-a1pyridinium dibromide (a) 1-amino-5,6,7,8-tetrahydro-2-phenylimidazo [1,2-a] pyridinium bromide.A solution of the N-amino compound of Example 2(b) (0.145 g.) in methanol (10 ml.) was hydrogenated over Adams catalyst at atmospheric temperature and pressure until the uptake of hydrogen ceased. The catalyst was filtered off, the solvent evaporated under reduced pressure and the residue crystallized from ethanol-ether giving the colourless bromide as the monohydrate, M.P. 156-159 (0.63 g.). The picrate crystallized from ethanol and had M.P. 133.

(b) 1,l -azobis[5,6,7,8-tetrahydro-2-phenyl-lH-imidazo [1,2-a]pyridinium]dibromide.A solution of the N- amino compound (0.06 g.) in water (5 ml.) was treated with saturated bromine water (15 ml.) and the precipitated red solid filtered off. The red solid was then boiled in acetone until the suspended solid became pale green. Filtration gave the dibromide (0.021 g.) which recrystallised from ethanol-ether as yellow prisms of the dihydrate which decolourised at 179-183 and melted at 259-262. The dipicrate crystallized from nitromethane as yellow prisms, M.P. 219.

EXAMPLE 10 1, 1 -azobis[ 2,3-dimethylbenzimidazolium] dibromide (a) 1-acetamido-2,3-dimethylbenzimidazolium iodide. -A solution of 1-acetamido-2-methylbenzimidazole (1.57 g.) in methyl iodide (10 ml.) was boiled under reflux for 24 h. Dry ether was then added to the cooled reaction mixture and the precipitated solid filtered E and recrystallized from ethanol-ether giving the iodide, M.P. 241.5-243.

(b) 1-amino-2,3-dimethylbenzimidazolium bromide- A solution of the iodide in 24% hydrobromic acid (20 ml.) was boiled under reflux for l h. The solution was then evaporated under rdeuced pressure and the residue crystallized from ethanolether giving the bromide monohydrate, M.P. 217 (0.51 g.).

(c) 1,1 -azobis 2,3 dimethylbenzimidazolium dibromide.A saturated aqueous solution of the bromide (0.55 g.) was treated with saturated bromide water (64 ml.) and the precipitated red oil triturated until solid. The red solid was filtered off and boiled with absolute acetone (20 ml.) and the resulting yellow solid filtered oif. Recrystallization from 48% hydrobromic acidacetone gave the dibromide hemihydrate, M.P. 239 (0.27 g.).

EXAMPLE l1 1,l -azobis[3-methyl-2,5-diphenylimidazolium] dibromide (a) 1-acetyl-2-benzimidoyl hydrazine-A solution of ethyl benzimidate hydrochloride (0.9 g.) in absolute alcohol (7.5 ml.) and triethylamine (0.7 ml.) was stirred at room temperature for 2 min. Dry Z acetylhydrazine (0.36 g.) was then added and the solution stirred for 48 h. The solution was then cooled in ice and the solid filtered 01f. Recrystallization from aqueous ethanol gave the colourless base, M.P. 168' (0.54 g.). The picrate crystallized from nitromethane and had M.P. 156-158".

(b) N-(2,5-diphenylimidazo-l-yl)acetamide.A mixture of the base (0.4 g.) and phenacyl bromide (0.225 g.) was dissolved in the minimum volume of boiling acetonitrile and the solution boiled under reflux for 2 h. The reaction mixture was then cooled in ice and ether added. The precipitated solid was filtered oil and crystallized from ethanol ether giving l-acetyl-2-benzimidoylhydrazine hydrobromide as white prisms, M.P. 204 (0.18 g.). The filtrate remaining after the removal of the hydrobromide was evaporated to dryness under reduoed pressure and the residual oil dissolved in benzene. Petroleum ether (6080) was added and the solution cooled. The separating solid was recrystallized from ethanol-benzene-petroleum ether (6080) giving the imidazole as white prisms (0.21 g.) which melted at 93.5-97 resolidified and finally melted at 183.

(c) 1-amino 2,5-diphenylimidazole.A solution of the acetamido compound (0.07 g.) in 24% hydrobromic acid (5 ml.) was boiled under refiux for 1.5 h. The solution was then evaporated under reduced pressure and the resulting white solid dissolved in water, basified with 2 N sodium hydroxide and the precipitated solid filtered The bromide thermally decomposes at 179-183 to form the hydrobromide of 5,6,7,8-tetrahydro-2-phenyllmidazo[1.241] pyridine, M.P. 270-27 3.

10 off. Recrystallization from aqueous ethanol gave the N- amino compound, M.P. 163.

(d) 1-amino-3-methyl 2,5 diphenylimidazolium bromide-A solution of the N-amino compound (0.1 g.) in a mixture of methyl iodide (5 ml.) and methanol (2 ml.) was boiled under reflux for 18 h. The solution was cooled and dry ether added. The precipitated gum was separated and triturated with ether until solid. Recrystallization from ethanol-ether gave the methiodide as pale yellow prisms, M.P. 188l89 (decomp) (0.13 g.). The methobromide obtained by ion exchange on Amberlite IRA400 (Br) crystallized from methanol-ether as colourless prisms, M.P. 162.5. The methopicrate crystallized from nitromethane-ether as yellow prisms, M.P. 159.

(e) 1,l -azobis[3-methyl-2,5 diphenylimidazolium1dibromide.--A solution of the bromide (0.06 g.) in the minimum volume of water was treated with saturated bromine water (10 ml.). The precipitated red oil was triturated until solid, filtered oil and boiled in absolute acetone (10 ml.). A further 10 ml. of acetone was added and the solution boiled again for a further 2 min. The solution was cooled as the tetrazene (0.03 g.) filtered oif and recrystallized from methanol ether giving yellow prisms, M.P. 199201. The dipicrate crystallized from intromethane-ether as yellow prisms, M.P. 2l5-216.

EXAMPLE 12 An injectable solution is as follows:

Percent w./v. Active ingredient (compound of Example 4) 2.72 Sodium chloride 0.63 Water for injections To What is claimed is: 1. A compound of the formula R and R which are the same or difl'erent, are each hydrogen, lower alkyl, halogen, phenyl, phenyl substituted by halogen, phenyl substituted by hydroxy, phenyl substituted by lower alkoxy, substituted by trilluoromethyl; phenyl substituted by nitro; or together with the adjacent carbon atoms to which they are attached form phenyl;

R and R which are the same or different, are each lower alkyl or phenyl, or together with the adjacent nitrogen atom form pyridinium or tetrahydropyridinium; and

X is a physiologically acceptable anion.

2. A compound as claimed in claim 1 in which R and R represent hydrogen, alkyl containing l-3 carbon atoms, halogen, phenyl or halophenyl and R and R together with the atoms of the imidazole ring form pyridinium or tetrahydropyridinium.

3. The compound as claimed in claim 1 which is 1,1 azobis[ lH-imidazo 1,2-a1pyridinium] dibromide.

4. The compound as claimed in claim 1 which is 1,1 azobis[2 phenyl-1H imidazo[l,2-a]pyridinium]dibromide.

5. The compound as claimed in claim 1 which is 1,1 azobis [3-bromo-2-methyl-1H imidazo 1,2-a] pyridinium] dibromide.

6. The compound as claimed in claim 1 which is 1,1 azobis[3-methyl-2-phenyl 1H imidaZo[1,2-a]pyridinium]dibromide.

7. The compound as claimed in claim 1 which is 1,1 azobis [3-br0mo 2-phenyl-1H-imidazo 1,2-a] pyridinium] dibromide.

8. The compound as claimed in claim 1 which is 1,1 azobis[2 (p bromoph'enyl) 1H-imidazo[l,2-a]pyridinium]dibromide.

9. The compound as claimed in claim 1 which is 1,1 -az0bis[2-methyl 3 phenyl-lH-imidazo[1,2-a]pyridinium] dibromide.

10. The compound as claimed in claim 1 which is 1,1 -azobis[2,3-diphenyl-1H imidazo[1,2-a]pyridinium] dibromide.

11. The compound as claimed in claim 1 which is 1,l -azobis[5,6,7,8 tetrahydro-Z phenyl-IH imidazo 1,2-a] pyridinium] dibromide.

12. The compound as claimed in claim 1 which is 1,1 -az0bis[2,3 dimethylbenzimidazolium]dibromide.

13. The compound as claimed in claim 1 which is 1,1 -az0bis[3-methyl 2,5 diphenylimidazolium1dibromide.

12 References Cited UNITED STATES PATENTS 3,409,606 11/1968 Lutz ct a1. 260-157 OTHER REFERENCES Kreutzberger, Chemical Abstracts, vol. 57, 5902-5903 (1962).

Gillcr et al., Index Chemicus, vol. 32, 108302 (1969).

Houben-Weyl, Mcthoden der Organischcn Chemie, vol. 10/2, pp. 828830 (1967).

McBride et al., J. Am. Chem. Soc., vol. 79, pp. 572- 576 (1957).

Overberger et al., J. Org. Chem., vol. 27, pp. 417-422 (1962).

FLOYD D. HIGEL, Primary Examiner U.S. Cl. X.R.

260293.78, 295 K, 296 L, 309, 561 H, 999; 424226 

